Estrogen is a “female hormone” whose various physiological activities have been described in a number of references (for instance, D. S. Loose-Mitchell and G. M. Stancel, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 10th Ed., J. G. Hardman and L. E. Limbird Eds, 2001, p. 1597-1634). In addition, estrogen regulates the development and function of the reproduction system, and affects a variety of physiological function (including maintenance of vaginal inner layer, retention of bone density and temperature regulation). In recent years, investigations showed that estrogen has a number of function other than physiological functions associated with female reproduction and genital tissue functions. On the other hand, in males, it is also known that estrogen is present in the body, and that the estrogen receptor is present in a variety of tissues (for instance, G Lombardi et al., Mol Cell Endocrinol, 2001, Vol. 178 (1-2), p. 51-55). In addition, estrogen decreases low density lipoproteins (LDLs) and regulates the production of cholesterol in liver. Furthermore, estrogen is thought to be involved in decreasing the risk of manifestation of Alzheimer's disease, and to alleviate the manifestation thereof (for instance, V. W. Henderson, Neurology, 1997, Vol. 48, (5 Suppl 7), S27-35).
Thus, estrogen is involved in a variety of functions in vivo, and when estrogen can no longer be produced, physiologically important alterations arise. Among others, estrogen production in healthy females is known to decrease sharply at menopause. Examples of effects of decrease in estrogen production include, in addition to the problems of urinary incontinence, vaginal dryness and decrease in skin tone, the problems of neurological symptoms, emotional instability and modulation of temperature regulation, as well as increase in blood lipid (leading to a large increase of the occurrence of cardiac diseases) and decrease in bone density (osteoporosis) and the like.
For example, in addition to urinary incontinence, vaginal dryness, increase in the rate of incidence of autoimmune diseases and loss of skin tone, problems related to the increase in the occurrence of autoimmune diseases, vasomotor complications (hot flashes), and neurological symptoms and the like, are symptoms which are associated with menopause, and are known to be alleviated or improved by estrogen replacement therapy.
However, estrogen administration leads to the increase of serious dangers such as breast cancer and endometrial cancer as well as thrombus formation.
A estrogen-dependent breast cancer is an example of pathological state associated with abnormal cell response to endogenous tissue estrogen. Estrogen-dependent tumor cells proliferate in the presence of estrogen. Current chemotherapies against these cancers largely rely on the use of anti-estrogen compounds, for instance, tamoxifen. Although such estrogen agonists-antagonists have beneficial effects in the treatment of these cancers and are acceptable in situations where adverse events of estrogen is life-threatening, they are not ideal. For instance, these agents, due to the estrogen (agonist) characteristics that they have, sometimes exhibit estrogenic stimulation of a group of cancer cells present in the uterus. A better therapy to treat these cancers is an agent, which is an anti-estrogen compound whose estrogen agonist characteristics may be ignored against the proliferating tissue or is completely inexistent.
Another estrogen-dependent symptom is uterine fibrosis (uterine fibroid tumor disease). This uterine fibrosis is fundamentally a state where a deposition of fibroid tissue is present on the uterine wall. This state is responsible for dysmenorrhea and infecundity in females. Except for the suggested evidence of an inadequate response of the fibroid tissue to estrogen, the exact cause of this state is not well known. The most general treatment of uterine fibrosis include surgical operations, which is expensive and sometimes cause complications such as abdominal adhesion and infection and the like.
In addition, another estrogen-dependent disease is endometritis, a serious dysmenorrhea state accompanied by sharp pain and hemorrhage into the endometrial mass or peritonea, often leading to infecundity. The cause for the occurrence of this state is thought to be the growth of a heterotropic endometrium present in an inadequate tissue, which respond inadequately to a normally hormonal regulation.
For a long time, estrogen replacement therapy has been practised for a number of important health problems caused by the inability to produce estrogen; however, due to an increase in the adverse effects and risks thereof, the use thereof became limited.
In addition, in case of problems related to osteoporosis caused by estrogen being no longer produced, one of the most general types of osteoporosis is associated with menopause. Here, osteoporosis means a group of diseases resulting from various causes of disease, and is characterized by the net loss of bone mass. This loss of bone mass and the resulting fracture lead to weakening of the skeleton that sufficiently maintains the body in structural terms. The majority of females lose approximately 20% to approximately 60% of bone mass in the trabecular constituent portion of the bone within 3 to 6 years after missed menstruation. Osteoporosis is a general and serious illness for postmenopausal females. Osteoporosis induces psychological damages to patients and family members; in addition, due to the chronical nature of this disease, large economical losses are sustained, and wide-range and lengthy care (hospitalization and home care nursing) is required due to the aftereffects of this illness. An excellent method for treating osteoporosis is estrogen replacement therapy (for instance, R. L. Prince et al., N. Engl. J. Med., 1991, Vol. 325, p. 1189-1195 and J. E. Compston, Physiol Rev, 2001, Vol. 81, p. 419-447). As mentioned above, estrogen therapy often provokes undesirable adverse effects, in particular in uterine and mammary tissues, the use of estrogen is limited, although this therapy has a therapeutic effect.
Further, in case of cardiovascular related problems, it has been long known that during the premenopausal period, the rate of incidence of cardiovascular illness for a majority of females is lower than males of the same age. However, at postmenopause, the rate of incidence of cardiovascular illness in females increases slowly in comparison to the proportion seen in males. This increase in rate of incidence is associated with a loss of estrogen, and particularly to a loss of estrogen that adjusts the serum lipid level. Postmenopausal females receiving estrogen replacement therapy have been reported to make their cardiovascular protection improve to a level that is equivalent to premenopausal state. Therefore, estrogen is thought to be a rational treatment for this state (for instance, M. E. Mendelsohn et al., N. Engl. J. Med., 1999, Vol. 340, p. 1801-1811). However, the adverse effects of estrogen replacement therapy cannot be accepted by a number of females, such that the use of this therapy is limited.
Meanwhile, Alzheimer's disease (hereinafter referred to as “AD”) is clinically a regressive neurodegenerative disease characterized by the gradual loss of memory, recognition, deduction, judgment and emotional stability, provoking gradually remarkable psychological depression and ultimately leading to death. AD is a general cause of progressive psychological impairment (dementia) in the elderly, and in the U.S. it is believed to be the 4th general medical cause of death. AD is observed in a variety of populations and ethnic groups in the world and represents a present and future major public health problem. The frequency of occurrence of this disease increases with age, and approximately 10% of the elderly population of 65 years and older is estimated to be affected (for instance, Evans et al., J. Amer. Med. Assoc., 1989, Vol. 262, p. 2551-2556). Thus far, AD has been shown to be incurable, and AD is expected to multiply in the world as human life span becomes longer.
Several studies in human have shown that the use of estrogen prevented the decline of the recognition function, then led to recovery (for instance, B. B. Sherwin, Psychoneuroendocrinology, 1988, Vol. 13, No. 4, p. 345-357 and T. Duka et al., Psychopharmacology, 2000, Vol. 149, No. 2, p. 129-139). Several epidemiological studies reported that the use of estrogen also decreases the risk of AD episode (for instance, V. W. Henderson, Neurology, 1997, Vol. 48, (5 Suppl 7), S27-35). In addition, estrogen appears to improve recognition function in AD patients (for, instance, Ohkura et al., Endocrine J., 1994, Vol. 41, p. 361-371 and V. W. Henderson, CNS Drugs, 1997, Vol. 8, No. 5, p. 343-351). Further, estrogen is known to possess an action of protecting nerve cells, which are beneficial to the treatment of neurodegenerative diseases such as AD, and an action of activating neurotrophic factors. However, the use of estrogen is also associated with a number of disadvantageous adverse effects including the increase in the risk of breast cancer and uterine cancer. It is possible that estrogen agonists or antagonists, while maintaining a large number of estrogen actions, lack adverse effects on tissues such as mammary gland and uterus.
Thus far, the discovery that a number of agents worked as estrogen agonists on some tissues (for instance, bone) and as antagonists on other tissues (for instance, mammary gland) provided effective treatments for symptoms provoked by a decrease in estrogen or estrogen-dependent diseases. Best known among these so-called selective estrogen receptor modulators (hereinafter referred to as “SERM”), tamoxifen, that is 1-(4-β-dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene, has been demonstrated to be therapeutically useful in the treatment and the prophylaxis of breast cancers, as well as in the decrease in LDL concentration. However, as tamoxifen simultaneously has an estrogenic stimulatory action on the uterus, it turned out to increase the risk of endometrial cancer.
In recent years, newer SERMs, for instance, raloxifene, that is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benz[b]thiophene, were reported to be, in regard to bone and lipid, similar to the desired action of estrogen, but in contrast to estrogen, uterine stimulation was minimal (for instance, Scrip, 1993, Apr. 16/20, No. 1812/13, p. 31 and Breast Cancer Research and Treatment, 1987, Vol. 10, No. 1, p. 31-36).
Raloxifene and related compounds are described as anti-estrogen substances and anti-androgen substances that are effective for the treatment of breast cancers and prostate cancers (for instance, U.S. Pat. No. 4,418,068 and Journal of Medicinal Chemistry, 1984, Vol. 27, No. 8, p. 1057-1066).
Other compounds such as those mentioned below are known as SERMs.
Derivatives of 2-phenyl-3-aroylbenzothiophene and 2-phenyl-3-aroylbenzothiophene-1-oxide, which are useful as contraceptive drugs and useful in inhibiting the growth of breast cancers, have been disclosed (for instance, U.S. Pat. No. 4,133,814).
An estrogen antagonist represented by the following formula;
(wherein R2 represents phenyl or cyclopentyl and R3 represents H,
or —CH2CHOHCH2OH) has been described (for instance, Journal of Medicinal Chemistry, 1969, Vol. 12, No. 5, p. 881-885).
Preparation of a series of tetrahydronaphthalenes intended to achieve the separation of estrogen activity, contraception activity, and hypocholesterolemia activity has been described. These structures are represented by the formula;
(wherein R1 represents H or OCH3; R2 represents H, OH, OCH3, OPO (OC2H5)2, OCH2CH2N(C2H5)2, OCH2COOH or OCH(CH3)COOH) (for instance, Journal of Medicinal Chemistry, 1967, Vol. 10, No. 2, p. 138-144).
An estrogen agonist and antagonist represented by the following formula;
have been disclosed (for instance, U.S. Pat. No. 6,204,286).
A compound represented by the following formula;
(wherein R3 represents a lower alkyl, R1 and R2 are selected from the group consisting of lower alkyls and 5 to 7 membered saturated heteocyclic ring formed by bonding lower alkyls to each other) has been disclosed (for instance, U.S. Pat. No. 3,274,213 and Journal of Medicinal Chemistry, 1967, Vol. 10, No. 1, p. 78-84).
An estrogenic compound represented by the following formula;
is disclosed (for instance, European patent application No. 802,183).
However, so far, there may be the current situation that no therapeutic agent exists, which is effective against symptoms caused by a decrease in estrogen and a variety of estrogen-dependent diseases and symptoms, furthermore, against central nervous system diseases including Alzheimer's disease. Therefore, there is a need for development of a compound that selectively has the activity which is an estrogen receptor modulator, and the property which is satisfactory as a desired medicine.